Abstract

Background: Uric acid is the final product of purine metabolism and elevated serum urate levels can cause gout. Conflicting results were reported for the effect of PKD2 on serum urate levels and gout risk. Therefore, our study attempted to state the important role of PKD2 in influencing the pathogenesis of gout. Method: SNPs in PKD2 (s2725215 and rs2728121) and ABCG2 (rs2231137 and rs1481012) were tested in approximately 5,000 Chinese individuals. Results: Two epistatic interactions between loci in PKD2 (rs2728121) and ABCG2 (rs1481012 and rs2231137) showed distinct contributions to uric acid levels with Pint values of 0.018 and 0.004, respectively, and the associations varies by gender and BMI. The SNP pair of rs2728121 and rs1481012 justly played roles in uric acid in females (Pint = 0.006), while the other pair did in males (Pint = 0.017). Regarding BMI, the former SNP pair merely contributed in overweigh subjects (Pint = 0.022) and the latter one did in both normal and overweigh individuals (Pint = 0.013 and 0.047, respectively). Furthermore, the latter SNP pair was also associated with gout pathology (Pint = 0.001), especially in males (Pint = 0.001). Finally, functional analysis showed potential epistatic interactions in those genes region and PKD2 mRNA expression had a positive correlation with ABCG2's (r = 0.743, P = 5.83e-06). Conclusion: Our study for the first time identified that epistatic interactions between PKD2 and ABCG2 influenced serum urate concentrations and gout risk, and PKD2 might affect the pathogenesis from elevated serum urate to hyperuricemia to gout by modifying ABCG2.